Antibiotic resistance is a growing problem that threatens human health globally. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) (see Pootoolal, J., et al., Annu. Rev. Pharmacol. Toxicol. 2002, 42, 381; and Raad, I. I., et al., Antimicrob. Agents Chemother. 2004, 48, 3583) are very dangerous and can be life threatening especially for patients whose immune systems have been compromised due to HIV, surgery or other illness. During the recent decades, the effort of discovering novel antibacterial agents has slowed down; in fact, oxazolidinones are the only new class of synthetic antibacterial agents over the past 30 years that possess totally new structures compared to existing antibacterial agents. See in this connection Brickner, S. J., Curr. Pharma. Design 1996, 2, 175; Diekema, D. J. and Jones, R. N., Lancet 2001, 358, 1975; Hollingsworth, R. I. and Wang, G., Kirk-Othmer Encyclopedia of Chemical Technology, Dec. 19, 2003; and Bozdogan, M. and Appelbaum, P. C., Int. J. Antimicrob. Agents 2004, 23, 113. The first compound of this class, Linezolid 1 (FIG. 1), was approved in 2000 for the treatment of multi-drug resistant bacterial infections including diseases caused by MRSA, VRE and Streptoccus pneumoniae. Oxazolidinones bind to the 50S subunit of the bacterial ribosome and inhibit protein synthesis at a very early stage by preventing the initiation of mRNA translation. Because they target the bacterial protein synthesis at an early stage, drug resistance was expected to be rare; however resistance to Zyvox (Linezolid) has already been reported (see Barbachyn, M. R. and Ford, C. W., Angew. Chem. Int. Ed. Engl. 2003, 42, 2010; and Hutchinson, D. K., Curr. Top. Med. Chem. 2003, 3, 1021).
Some structures of the existing small molecule antibacterial agents are shown in FIG. 1. These include Linezolid (1), Ciprofloxacin (2), Sulfonamide (3) and Chloramphenicol (4). The very general features of these agents are that they all contain aromatic and/or heterocyclic structures and they have heteroatom substituents such as halo, amino and/or hydroxyl groups. Linezolid has oxazolidinone as its core structure, which is important for its activity. Ciprofloxacin is one example of the fluoroquinolone class of antibiotics. See in this connection Higgins, P. G., et al., Curr. Drug Targets 2003, 4, 181; Zhanel, G. G., et al., Drugs 2002, 62, 13; Drlica, K. and Malik, M., Curr. Top. Med. Chem. 2003, 3, 249; Chen, Y.-L., et al., J. Med. Chem. 2001, 44, 2374; Hu, X. E., et al., J. Med. Chem. 2003, 46, 3655. They kill bacteria by inhibiting DNA gyrase enzyme which is essential for DNA replication. The structure of ciprofloxacin contains a fused aromatic ring with a fluorine substituent and a polar piperazine substituent. Sulfonamide contains phenyl sulfonyl phenyl amines. The sulfonamides are inhibitors of the bacterial enzymes required for the synthesis of tetrahydrofolate (see Masters, P. A., et al., Arch. Internal Medicine 2003, 163, 402), an essential nutrient for bacterial growth. Chloramphenicol contains substituted nitrophenol with dichloromethyl acetamido functional groups. It also inhibits bacterial protein synthesis and is a broad spectrum antibiotic for both Gram positive and Gram negative bacteria, but chloramphenicol has some serious side effects (see Mitscher, L. A., et al., Med. Res. Rev. 1999, 19, 477).
Many new antibacterial agents are designed based on modification of the existing structural classes; since the antibiotic assay is easy to carry out, the modes of action of the agents often are discovered after finding them active.
It would be desirable to have a novel class of compounds which shows antibacterial activity, and especially compounds that show a high level of antibacterial activity.